Title : Chronic amphetamine exposure during development causes epigenetic and behavioral effects in adult animals and progeny
Abstract:
Amphetamine (AMPH) is used as psychostimulant, appetite suppressant and to treat Attention Deficit Hyperactive Disorder (ADHD). Among other effects, AMPH has been shown to alter the function of proteins uniquely associated with the reward system, i.e. the dopamine transporter (DAT). Similarly to mammals, the nematode Caenorhabditis elegans (C. elegans) exhibits changes in behaviors when treated with AMPH, and we showed that these AMPH-induced changes are in part mediated by the C. elegans DAT (DAT-1). Since AMPH is used, either as recreational drugs or therapeutically for extensive periods, we investigated the long-term effects of AMPH by treating chronically C. elegans embryos with AMPH or control solution, and then challenged adult animals with one dose of AMPH during a behavioral assay. We found that in the group which received AMPH during development, the number of adult animals exhibiting AMPH-induced behaviors was higher than the group that was exposed to control solution. Interestingly, we found that the behavioral effects caused by AMPH exposure during development were transmitted to progeny. Because DAT-1 is one of the proteins required to generate AMPH-induced behaviors in C. elegans, we tested whether embryonic exposure to AMPH alters expression of the dat-1 gene in adults and progeny. Among other epigenetic mechanisms, histone methylation has been shown to be altered by drugs of abuse. Thus, we investigated whether AMPH changes the methylation status of the histone 3 (H3) at the promoter of dat-1. ChIP assays showed a significant decrease of the level of trimethylation at the lysine 4 of H3 (H3K4me3) and an increase of H3K9me2 at the promoter of dat-1 of adult animals and progeny whose parental lines were exposed to AMPH during development. As H3K4me3 and H3K9me2 are associated with gene activation and inactivation respectively, our data suggest that AMPH treatment during early development causes long-term and transgenerational depression of the dat-1 gene expression. These results were supported by functional studies showing a significant decrease in [3H]DA uptake in primary cultures from embryos (F1 generation) originated from animals exposed to AMPH during development (F0 generation) with respect to control cultures.
Take away:
Because many of the components of the dopaminergic system as well as epigenetic mechanisms are highly conserved between C. elegans and mammals, these results could be critical for our understanding of how drugs of abuse initiate and promote addiction in adults and future generations.
